Ruchira M. Jha

Pilot Case-control Investigation of Risk Factors for Hip Fractures in the Urban Indian Population

BackgroundDespite the reported high prevalence of osteoporosis in India, there have been no previous studies examining the risk factors for hip fracture in the Indian population.MethodsWe carried out a case control investigation comprising 100 case subjects (57 women and 43 men) admitted with a first hip fracture into one of three hospitals across New Delhi. The 100 controls were age and sex matched subjects who were either healthy visitors not related to the case patients or hospital staff. Information from all subjects was obtained through a questionnaire based interview.ResultsThere was a significant increase in the number of cases of hip fracture with increasing age. There were significantly more women (57%) than men (43%). Univariate analysis identified protective effects for increased activity, exercise, calcium and vitamin supplements, almonds, fish, paneer (cottage cheese), curd (plain yogurt), and milk. However, tea and other caffeinated beverages were significant risk factors. In women, hormone/estrogen therapy appeared to have a marginal protective effect. For all cases, decreased agility, visual impairment, long term medications, chronic illnesses increased the risk of hip fracture. The multivariate analysis confirmed a protective effect of increased activity and also showed a decrease in hip fracture risk with increasing body mass index (odds ratio (OR) 0.024, 95% confidence interval (CI) 0.006-0.10 & OR 0.81, 95% CI 0.68-0.97 respectively). Individuals who take calcium supplements have a decreased risk of hip fracture (OR 0.076; CI 0.017-0.340), as do individuals who eat fish (OR 0.094; CI 0.020-0.431), and those who eat paneer (OR 0.152; 0.031-0.741). Tea drinkers have a higher risk of hip fracture (OR 22.8; 95% CI 3.73-139.43). Difficulty in getting up from a chair also appears to be an important risk factor for hip fractures (OR 14.53; 95% CI 3.86-54.23).ConclusionsIn the urban Indian population, dietary calcium, vitamin D, increased body mass index, and higher activity levels have a significant protective effect on hip fracture. On the other hand, caffeine intake and decreased agility increase the risk of hip fracture. Future studies should be done in order to direct primary preventive programs for hip fracture in India.

Palliation of compression fractures in cancer patients by vertebral augmentation: a retrospective analysis

Aim To evaluate the efficacy of vertebral augmentation (VA) in cancer patients. Materials and methods From a retrospectively compiled database, 147 cancer cases (236 levels) were treated with VA. Mean age was 71±12 years and 56.5% were female. Variables evaluated include age, sex, procedure type, vertebral level treated, number of levels treated per procedure and technical approach. Outcomes were assessed by a previously described method retrospectively applied from medical records: a binary system of ‘responders’ versus ‘non-responders’ and further subcategorization with a four level pain scale. Two patient groups were analyzed: (1) 147 cancer patients with either osteoporotic or malignant vertebral compression fractures (all compression fractures (ACFs)) and (2) 102 cases with documented metastatic compression fractures (MCFs). Univariate and multivariate analyses determined outcomes. Results 93% of MCFs and 88.5% of ACFs showed response to treatment (pain improvement or resolution): 30% of ACFs and 31% of MCFs experienced pain resolution. MCFs showed increasing age to be a predictor of response to treatment in univariate (OR=1.79, p=0.04) and multivariate (OR=2.05, p=0.03) analysis. In ACFs, bipedicular needle approach decreased the odds of pain resolution (OR=0.28, p=0.01). In MCFs, lung cancer (OR=0.06, p=0.03) and multiple myeloma (OR=0.10, p=0.01) decreased the odds of pain resolution. Conclusions VA provides pain relief for a majority of ACFs and MCFs. Increasing age may be predictive of pain relief outcomes in MCFs. There are special planning, imaging and technical considerations (eg, needle placement) in using VA to treat cancer patients.

The Isolation, Differentiation, and Survival In Vivo of Multipotent Cells from the Postnatal Rat filum terminale

Neural stem cells (NSCs) are undifferentiated cells in the central nervous system (CNS) that are capable of self-renewal and can be induced to differentiate into neurons and glia. Current sources of mammalian NSCs are confined to regions of the CNS that are critical to normal function and surgically difficult to access, which limits their therapeutic potential in human disease. We have found that the filum terminale (FT), a previously unexplored, expendable, and easily accessible tissue at the caudal end of the spinal cord, is a source of multipotent cells in postnatal rats and humans. In this study, we used a rat model to isolate and characterize the potential of these cells. Neurospheres derived from the rat FT are amenable to in vitro expansion in the presence of a combination of growth factors. These proliferating, FT-derived cells formed neurospheres that could be induced to differentiate into neural progenitor cells, neurons, astrocytes, and oligodendrocytes by exposure to serum and/or adhesive substrates. Through directed differentiation using sonic hedgehog and retinoic acid in combination with various neurotrophic factors, FT-derived neurospheres generated motor neurons that were capable of forming neuromuscular junctions in vitro. In addition, FT-derived progenitors that were injected into chick embryos survived and could differentiate into both neurons and glia in vivo.

The Postnatal Human Filum Terminale Is a Source of Autologous Multipotent Neurospheres Capable of Generating Motor Neurons

BACKGROUND Neural progenitor cells (NPCs) are undifferentiated and mitotic and can be induced to differentiate into neurons and glia, the building blocks of the nervous system. NPCs have great therapeutic potential for nervous system trauma and degenerative disorders. They have been identified in the mammalian central nervous system, but current sources are difficult to access surgically and come from regions that are critical for normal brain function. OBJECTIVE To identify and characterize in detail a novel source of human NPCs in the filum terminale (FT), a vestigial structure at the caudal end of the spinal cord, which is easily accessed and plays no functional role in the postnatal nervous system. METHODS Cells were isolated and cultured in vitro from the FT of terminated fetuses and from children and adolescents who had undergone surgical resections for tethered spinal cords. Cell culture techniques, immunohistochemistry, and immunocytochemistry were applied to examine FT cells. RESULTS : FT cells gave rise to neurospheres that proliferated over extended periods of time in culture. These neurospheres were positive for neural stem/progenitor cell markers by immunocytochemical staining. The neurospheres were able to be induced to differentiate in vitro into neurons and glial cells, which were confirmed by the use of antibodies against the cell type-specific markers. Moreover, they have been induced to form motor neurons capable of innervating striated muscle in vitro. CONCLUSION Multipotent NPC cells from the FT are both accessible and expendable. They may allow autologous cell-based transplantation therapy that circumvents immunological rejection.

Practical management of malignant compression fractures

Vertebral augmentation (VA) is a minimally invasive, imaging-guided procedure with deep roots in the NeuroInterventional community. In the USA, this procedure has been performed primarily for painful osteoporotic compression fractures. Despite studies supporting its efficacy in malignant spinal fractures, it remains underutilized for this population of patients.1 One of the ironies of this development is the often forgotten fact that the first patient treated at the University of Virginia had metastatic breast cancer. Because of the fear of tumor displacement during treatment and potential compressive neurological compromise, our early experience was characterized by: (1) advocating external beam radiation therapy in advance of treatment; (2) quoting to the patient a ‘relatively high’ 5%–10% procedural complication rate; (3) performing adjunctive procedures such as concurrent myelography to ensure no change in spinal canal patency during balloon inflation (for kyphoplasty) and polymethylmethacrylate (PMMA)deposition (for kyphoplasty and vertebroplasty). While such concerns are well intentioned, they lead to a reluctance on the part of practitioners to extend this therapy to cancer patients in need. The accompanying article may ameliorate some of these concerns and provides a substrate for cautious enthusiasm. Our retrospective 5-year cohort suggests that cancer patients with vertebral compression fractures (VCFs) can achieve meaningful pain control from VA with an acceptably low risk of complication. We recognize the limitation of this type of retrospective analysis and look forward to the publication of the Cancer Patient Fracture …

Clinical Anatomy and Imaging of the Cranial Nerves and Skull Base

Evaluation of patients with cranial neuropathies requires an understanding of brainstem anatomy and nerve pathways. Advances in neuroimaging, particularly high spatial resolution magnetic resonance imaging (MRI), have enabled visualization of these tiny structures and their related pathology. This review provides an approach toward using imaging in the evaluation of cranial nerve (CN) and skull base anatomy and pathology. Because brainstem nuclei are inextricably linked to the information contained within CNs, they are briefly mentioned whenever relevant; however, a comprehensive discussion of brainstem syndromes is beyond the scope of this review.

Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury

Objective ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. Methods DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs. Results Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene. Conclusions This study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Characterization of the Filum terminale as a neural progenitor cell niche in both rats and humans

Neural stem cells (NSCs) reside in a unique microenvironment within the central nervous system (CNS) called the NSC niche. Although they are relatively rare, niches have been previously characterized in both the brain and spinal cord of adult animals. Recently, another potential NSC niche has been identified in the filum terminale (FT), which is a thin band of tissue at the caudal end of the spinal cord. While previous studies have demonstrated that NSCs can be isolated from the FT, the in vivo architecture of this tissue and its relation to other NSC niches in the CNS has not yet been established. In this article we report a histological analysis of the FT NSC niche in postnatal rats and humans. Immunohistochemical characterization reveals that the FT is mitotically active and its cells express similar markers to those in other CNS niches. In addition, the organization of the FT most closely resembles that of the adult spinal cord niche. J. Comp. Neurol. 525:661–675, 2017.

Hemorrhagic primary CNS angiitis and vasoconstrictive drug exposure

Background: Primary angiitis of the CNS (PACNS) typically manifests with accumulating neurologic deficits from ischemic strokes. Intracerebral hemorrhage (ICH) is an uncommon complication. There is limited knowledge about the risk factors and features of hemorrhagic PACNS. Methods: We identified 49 patients (20 biopsy-proven) with PACNS diagnosed at our hospital from 1993 to 2015. We compared the features of hemorrhagic and nonhemorrhagic PACNS and analyzed the hemorrhagic PACNS cases in detail. Results: The mean age was 51 ± 15 years; 13 patients were men. Five patients had ICH (mean age 52 ± 14 years; 4 men) including 4 where ICH was the first manifestation of PACNS. All ICH patients reported recent exposure to sympathomimetic drugs (e.g., diet pills, nasal decongestants). Patients with ICH had higher rates of headache (100% vs 43%, p = 0.022), especially thunderclap headache (60% vs 0%, p = 0.001), and eosinophilic vascular infiltrates on brain biopsy (50% vs 9%, p = 0.084). In all ICH patients, brain MRI showed lobar hemorrhages with concurrent punctate diffusion-restricted lesions, suggesting an acute inflammatory process. Four received a short course of immunosuppressive therapy. All patients showed complete clinical resolution or significant improvement within weeks. Conclusions: In this study, hemorrhagic PACNS was exclusively associated with sympathomimetic drug exposure. The high rate of thunderclap headache, lobar hemorrhages, and the self-limited clinical course suggests a shared mechanism between hemorrhagic PACNS and the reversible cerebral vasoconstriction syndrome (RCVS), a PACNS mimic. This RCVS-PACNS overlap syndrome may result from sympathomimetic drug–induced prolonged distal vasoconstriction, culminating in inflammation.

The Safety and Effectiveness of a Curved Needle for Vertebral Augmentation: Comparison with Traditional Techniques

PURPOSE To evaluate the safety and effectiveness of a curved needle compared with traditional (noncurved needle) techniques in a large single-center experience. MATERIALS AND METHODS This study was a retrospective analysis of 243 consecutive vertebral augmentation procedures over a 17-month period. Curved needle procedures were compared with noncurved needle procedures for baseline clinical variables, complication rate, pain relief, and improvement in disability. Procedure duration and fluoroscopy time were compared between the two cohorts. RESULTS Between curved needle and noncurved needle procedures, there were no statistically significant differences in the baseline clinical variables, fracture location, and fracture etiology. No complications were noted in either group. In both groups, there was a median improvement in the visual analog scale (VAS) score of 2.0 points (P = .62). More than 90% of procedures in both groups resulted in some pain improvement (P = .78). For both groups, the median improvement in disability on the Roland Morris Disability Questionnaire (RMDQ) was 4.0 points (P = .69). Approximately 70% of procedures in both groups resulted in improvement in disability (P = 1.00). In single-level cases, there were shorter procedure times (51.8 min ± 2.7 vs 62.8 min ± 2.2, P = .002) and shorter fluoroscopy times (P = .31) for curved needle procedures. CONCLUSIONS The curved needle is as safe and effective as traditional vertebral augmentation techniques in treating the pain and disability related to vertebral compression fractures. Additionally, the curved needle is associated with shorter procedure duration and reduced fluoroscopy time.